{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:04:56Z","timestamp":1760148296846,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Commission FP7 Program (Brussel, Belgium)","award":["HEALTH-2013-6029047","SFB1470"],"award-info":[{"award-number":["HEALTH-2013-6029047","SFB1470"]}]},{"name":"TEVA Ratiopharm (Vienna, Austria)","award":["HEALTH-2013-6029047","SFB1470"],"award-info":[{"award-number":["HEALTH-2013-6029047","SFB1470"]}]},{"name":"DFG Collaborative Research Center (Berlin, Germany)","award":["HEALTH-2013-6029047","SFB1470"],"award-info":[{"award-number":["HEALTH-2013-6029047","SFB1470"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet\u00ae, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, \u00df-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF.<\/jats:p>","DOI":"10.3390\/ijms24087461","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T01:39:05Z","timestamp":1681868345000},"page":"7461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8040-8086","authenticated-orcid":false,"given":"Dominika","family":"Lukovic","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ena","family":"Hasimbegovic","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Winkler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1426-6670","authenticated-orcid":false,"given":"Julia","family":"Mester-Tonczar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-7643","authenticated-orcid":false,"given":"Katrin","family":"M\u00fcller-Zlabinger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-1277","authenticated-orcid":false,"given":"Emilie","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9819-0361","authenticated-orcid":false,"given":"Andreas","family":"Spannbauer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-1525","authenticated-orcid":false,"given":"Denise","family":"Traxler-Weidenauer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jutta","family":"Bergler-Klein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noemi","family":"Pavo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Goliasch","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandor","family":"Batkai","sequence":"additional","affiliation":[{"name":"Hannover Medical School Institute of Molecular and Translational Therapeutic Strategies (IMTTS), 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4360-1511","authenticated-orcid":false,"given":"Thomas","family":"Thum","sequence":"additional","affiliation":[{"name":"Hannover Medical School Institute of Molecular and Translational Therapeutic Strategies (IMTTS), 30625 Hannover, Germany"},{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Inserm Clinical Investigation Centre, Universit\u00e9 de Lorraine, CHU, 54052 Nancy, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7083-2107","authenticated-orcid":false,"given":"Mariann","family":"Gy\u00f6ngy\u00f6si","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"ref_1","first-page":"502","article-title":"Porcine Model of Progressive Cardiac Hypertrophy and Fibrosis with Secondary Postcapillary Pulmonary Hypertension","volume":"15","author":"Pavo","year":"2017","journal-title":"J. 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